My long-term goal is to become an independent investigator in the field of obesity, particularly in the area of regulation of substrate metabolism. I am currently completing my post-doctoral training under the direction of James O. Hill, Ph.D., an international leader in obesity research, and director of the Colorado Clinical Nutrition Unit (CNRU) at the University of Colorado Health Sciences Center (UCHSC). With guidance from my sponsor (Dr. Hill) and mentors (Wendy Kohrt, Ph.D, Tracy Horton, Ph.D, and Robert Eckel, M.D.), 1have developed a comprehensive career plan consisting of a) a structured didactic training program to increase my knowledge base; and b) a mentored research project, where the primary aims are a) to determine whether fat metabolism (lipolysis and/or oxidation) is impaired in obesity, and b) whether this can be reversed with weight loss. Exercise is advocated for obesity treatment, presumably through its potential to increase fat oxidation, but appears to have limited effectiveness. Evidence suggests that fat oxidation is blunted in obese and weight-reduced obese (WRO) subjects during exercise. This impairment may be inversely related to exercise intensity, and more apparent when subjects are studied in the fed vs. fasted state. Thus, secondary aims are to determine in obese and WRO humans whether fat metabolism during exercise is influenced by a) exercise intensity; or b) feeding state (fasted vs. post-prandial). A final aim is to explore the relationship between fat oxidation (whole-body and in vitro skeletal muscle fat oxidation capacity) and a) circulating factors the regulate fat oxidation (leptin, adiponectin); and b) the expression of factors (PPARa) and proteins (e.g. UCP-3) that regulate fat metabolism within skeletal muscle. The driving hypotheses are that a) fat metabolism is impaired in obese and weight-reduced obese (WRO) humans; and b) these impairments are not reversed by weight loss. To test these hypotheses, I will take advantage of unique resources available through the CNRU Core Labs, particularly, whole-room indirect calorimetry, stable isotope technology, and molecular biology. Understanding how exercise regulates fat metabolism in obese and WRO individuals is crucial in understanding the physiology of body weight regulation. I believe the results from these studies will lead directly to additional studies to further explain why exercise may be important in the prevention and treatment of obesity.